Live chat with Dr. Jason Hawrelak

My name is Alex Aharikis and We're here with Dr. Harlick. We're going to be talking about the microbiome and I think it's going to be a really interesting presentation. So definitely want to catch it if you're not watching it live. So I'll do a brief introduction for Dr. Harlick. He's a researcher, educator and nutritionist, naturopathic physician with over 20 years experience clinically helping patients with gastrointestinal issues. He did his PhD examining the capacity of probiotics, prebiotics and herbal medicines to modify the gut microbiota and teaches widely both in Australia and internationally on these topics. He has published extensively, including 20 textbook chapters. Dr. Horlick is on the Medical Nutrition Council of the American Society for for Nutrition and is a fellow of both the American College of Nutrition and the Naturopaths and Herbalists association of Australia. He's also a visiting research fellow at the Australian Research center for Complementary and Integrative Medicine at the University of Technology in Sydney, Australia. Dr. Horlick has taught health professionals at both the undergraduate and postgraduate level for the past 20 years. He is currently the senior Lecturer in complementary and alternative medicines. And at the University of Tasmania he coordinates the evidence based complementary medicine programs and also teaches natural approaches to gastroenterology. Dr. Harlick is Chief Research Officer at Probiotic Advisor. Probiotic advisor.com which is a surgical database for evidence based prescribing of probiotic products and resources for clinicians and members of the public. Definitely check that out. In today's live chat we'll discuss various mechanisms, treatment alternatives and available tests, environmental factors and supplements to promote a healthy microbiota for people with autism and other disorders. Dr. Horlick, welcome. How are you?

I'm good. Good day Alex, how are you going today?

Great. Yeah. So you know we're going to have this of be a fluid discussion. I have some questions. We had some questions come in but basically we want to talk about the microbiome as it relates to autism. It seems to be a significant component in people with autism having dysbiosis and gut problems. So I'll start with some simple questions but basically I wanted to push it to you to talk about, you know, what, what do you do in your practice, what kind of patient do you treat typically? You know, what's your methodology? What types of patients outside of autism might you counsel and advise?

Okay, yeah. I mean I've been in clinician for 21 years now. It makes me feel old when I say that it's going by pretty, pretty quickly. And I was lucky to essentially choose to his PhD topic which was looking at how you modify the microbiota using prebiotics, probiotics, her medicines back in since it was 2000, you know. So for me a core part of my clinical practice because I maintain teaching, I've maintained clinical practice and researching that the entire time. There's sort of three, three threads are really much part and parcel of my life still. But lucky for me, luckily I chose that topic area and it meant that modifying the microbiota has been a key part of my treatment approach to any disease state that I'm actually working with with patients for that 20 years. And it's just been fantastic to see the evolution of tools as a clinician that give us more accurate pictures of what's going on and as well as research linking microbiot alterations, dysbiosis with a wider range of disease states than we ever remotely considered possible 20 years ago. And that's been fantastic. So my practice, I certainly treat kids from the spectrum but most it's git related issues. So inflammatory bowel disease, irritable bowel syndrome, sibo, chronic constipation, peptic ulcer disease, Helicobacter pylori, intestinal parasites, those would make up the vast, vast majority of patients and you've got others who would have chronic fatigue or chronic depression that are linked or fibromyalgia that I think definitely have strong links to gut dysphoric patterns and dysfunction in the gastrointestinal tract as well. And even conditions like anxiety and depression, which I still think have a core, a core underlying driver in many patients is gut dysfunction and dysbiosis.

Okay, awesome. In terms of, you know, microbiome testing, I feel like that this is really kind of taken off in the last couple of years. You know, in particular it's gotten more mainstream that the public can, can get into it. Can you give us the pros and cons of maybe some of the tests that you like that you dislike? What are the differences between them, you know, pcr is there ones that people on the spectrum should look towards to being more accurate or just being more helpful in general?

Yeah, great question. And, and this has been interesting journey for me in the last 21 years watching the changes in technology from evolve for assessing the microbiome because when I started it was still culturing where people would you know, take poo samples and put it out and plate out like hundreds different sort of petri dishes to try to see what was growing there. And researchers at that time were acknowledging that this was not the best way of doing it. We were probably missing lots of species and certainly over the next 10 years that was proven to be totally correct. So when we switched to using DNA technologies, molecular techniques, we started seeing that the ecosystem was far, far more complex than what we thought in the 1990s. And potentially with some patients, 70% of the ecosystem composition could not be grown using old techniques, but using DNA techniques, we can see that they're there. And that has allowed this field to, to, to blossom and boom, the way that actually has and allowed us to start making those different links that we have in the last 15 years. And I think when it comes to. Yeah, so I think you can, you can kind of divide stool tests up into culturing. And these are the old style, comprehensive digestive stool analyses, type tests or fecal microbial analyses that are based on culturing. They really have a extremely limited role to play in determining what's happening in the gut because they can't see most of what's there. Even if they were done comprehensively, they can't see much of what's there. And they're not. Ones that are done clinically might look for six species or eight species of bacteria and out of 160 that might be present, I mean, you're not getting a very good representation of what's there. So I think that whilst those tests, like cdsas, can provide useful markers around inflammatory, you know, levels of gut inflammation, digestive markers, immune markers, short chain fatty acids, stool ph, things that fundamentally useful, their capacity to detail the ecosystem are extremely limited and shouldn't be considered to be remotely valid to do that. So that leaves us with molecular techniques. And I would say that there are three types of tools, broadly speaking, that we have access to as general public or clinicians, to assess the microbiome biota using molecular techniques. We've got PCR, we've got 16s RRNA sequencing and then we have shotgun metagenomic sequencing and I can probably talk a little bit about each one. Now, PCR has got some strengths and the strength of pcr, again, still looking at bits of bacterial DNA, or it can look at fungal DNA or protozoal DNA as well. That's one of the strengths, is that you can look at those different bits and you can quantify and if done well, you can quantify with it as well and get an actual number of bacteria per gram of poo. But one of the limits, really the limits are, is that you only see what you're looking for, and that if you're looking for your PCR probe is for E. Coli, you're just looking for E. Coli. And each test will be limited by the number of different species that they look for. So what PCR doesn't give you is a comprehensive view of the entirety of the ecosystem, terms of all the species that are present, their balance, their evenness of distribution. You really can't get any idea around a couple of really important components when we're talking about ecosystem health. And how do we define a healthy ecosystem? This is still being debated among research scientists, I can assure you, but I think there's a few things that after 20 years in the field is what I look for. One is the diversity, that ecosystem. So how. And that is composed of two markers. One is the richness of the ecosystem. So how many species are present, how many genera are present, how many species within the genera, and even arguably how many strains there are within those species. That can give you an idea of how diverse an ecosystem is in terms of richness, but then how evenly spread they are too. Because what you don't want is having one species that dominates at 60, 70, 80% of an ecosystem. And you can't see those details using pcr. You can't. And that, to me is really problematic. Whereas you can see those details when you're looking using 16s techniques, which give you a lovely snapshot of the entire bacterial component of the ecosystem, everything that's there. Whereas I said the other limitation. With PCRs, they're only looking for what they're looking for. So if they don't have, if they're not looking for, to Sulfovibrio or Bilophylla or Rheumatococcus, it won't show up even though they have it. Yeah, and I think that's one of the limitations. But with 16s, you see the whole thing. And then with shotgun metagenomic sequencing, again, you see the whole thing. But one of the strengths of shotgun is that you. They're. They're taking out all the DNA and separating it out and going, okay, here's bacterial DNA, here's fungal DNA, here's protozoal DNA, here's viral molecules, so rna. So they can actually you get a very comprehensive look at the ecosystem far more broadly, because it takes into account things like fungi, protozoa that we don't see with 16s. So labs that use 16s are the previous ubiome that many people would have had done that, that has since died. But other Labs like, you know, American Gut Project 3 Thrive Biome Site, Somagen Gene and Gut Biome are ones that use 16s techniques. And then shotgun techniques are used by labs here in Australia called Microba and Cosmos ID in the US that runs through their Nevada Biome interface. And then labs like microbiome labs. BiomeFX also uses Cosmos ID for their tests as well. Now VIOME also uses Shotgun, but you don't get a comprehensive report from in terms of composition. So whilst Biome, the technology they're using is totally acceptable for me as a clinician, the reports are of limited usefulness to determine what the ecosystem is composed of. So I put them in a slightly different category. Yeah, and what all three of those shotgun PCR or 16s, they will tell us generally levels of, you know, the other aspects of healthy ecosystem composition that I want to look at and that's levels of beneficial bacteria, levels of pathobiots and levels of pathogens. Okay. But I'd say that PCR tests that we, that are generally really marketed are really much focusing on the pathogens. You know, there's one test that's really widely used that has eight species of normal bacteria within three pages full of pathogens that it's looking for. And I think it can, it can throw you down the wrong track using tests like that because you become so obsessed finding pathogens that you don't look at the broader ecosystem and the test doesn't tell you much about the actual ecosystem itself. So I think that can be another limitation with PCR that we don't have with 16s or shotgun, which give us a much bigger and more accurate and comprehensive picture of, of beneficial bacteria, pathogens and pathobiomes because if they're there, they show up. Whereas pcr, as I said, the limitations, it only sees what it's looking for.

Okay, awesome. What in terms of like the reproducibility? Because this has always been a question in my mind, you know, if I were to send the same sample to the same lab twice, you know, would I get the same result? Is there, you know, variability in just the, the physics and the biology of doing the test or is it just me not getting the sample, you know, as I'm probing this piece of stool, you know, is the inherent, you know, variability in that, does it matter?

Well, good questions. I think if you're staying within, within ecosystems of lab testing, I think you're more actually be able to compare testing to previous tests, to current tests. And by that I mean stay with 16. If you got 16s. Stay with 16s rather than going, okay, well skip over to shotgun and then try to compare because there'll be differences in technology that could explain some of the differences that you're seeing that aren't actually real differences between them. So I think, I think that's one point I want to make too. In terms of the same stool sample, the same lab, I reckon, and I have had patients do this before, is you get very similar results and you've had sometimes the same patient sending, sending one weekly, assuming they haven't changed the diet, they haven't changed their lifestyle, no new medications, etc, very, very consistent across, across that. I certainly have seen that. But if when people send one sample, and I've done this experiment to one sample, to five different labs using different technologies, sometimes the results can just be mind blowingly different, which is a little bit worrying as well, because you're making just prescribing decisions based on that. And depending on what lab you're choosing, you might end up getting quite different results and then treating things quite differently. Now, in terms of the optimal fecal sampling technique, there was a research study that I've come across that was compared essentially collecting the entire fecal specimen in a Ziploc bag and then mushing it all together and then sampling from the middle of that and comparing that to just touching the toilet paper. And most of the labs these days just do the touching to toilet paper because it's easy and they only is very small specimen. So you know that, that suffices. And people are generally pretty poo phobic, so touching toilet paper with a little sticky thing is probably okay, but mixing the bag isn't. But the results of study show that you get a more accurate picture if you actually take the whole specimen and mush it up and take it for the middle. So for my patients who are less, who are not poo phobic, who are quite okay with dealing with poo, handling poo, I usually suggest that option to get the most accurate picture of its entirety because you can sometimes get differences in different parts of the stool, which does make things a bit more complicated.

Just want to go off topic quickly. We had a question come across and I don't want to forget it. The question was the impact of Borrelia lime in the microbiome. In the microbiome? What, what potential impact, you know, would that have? It kind of contributed dysbiosis. I mean, is that something that you've seen?

Well, I should. The biggest caveat here is that I practice In Australia, where our Lyme is arguably not present, or if it is, it's very infrequent and, and the number of patients that I would have that, that would present with Lyme would be pretty small. So that limits my experience as a clinician who does lots of stool assessments to see any sort of pattern that might be there. And to the best of my knowledge at least, I've never seen any papers that have discussed the impact of Lyme on the gut microbiota. I think it's unlikely they've been published. And so I'd say there's lots of unknowns there. But if things alter things, that can alter the gut floor composition. So if Lyme disease impacted, and again, I don't treat these patients, so. And I don't know much about the pathophysiology and how it may express in different patients, but if it's impacted transit time, either sped it up or slow transit time, that, that could impact bacterial populations, you know, if it, if it caused some sort of inflammation in the nerves and the gut. And again, I don't. Can't say for sure or not whether this does that or not, but just during putting forth hypotheses of how it could possibly change things in a more indirect way by essentially changing digestive tract function.

Okay, that's actually interesting because I think that's a good leeway into the next question was going to be, you know, dysbiosis in autism. And, you know, typically what we see as parents is kind of extremes where you might have a child that is extremely constipated, that might not have a bowel movement for days, and then you can have the complete opposite end of the spectrum and even understand that constipation might not necessarily be associated purely with, you know, the frequency that you're going to the bathroom, but you might have seven or eight different stools in a particular day. And if you were to quantify dysbiosis and autism, what would you say is out of balance? What do you typically see and how might that dysbiosis impact the child or the patient to cause either some kind of brain inflammation through that gut brain axis, you know, how does that physically happen? How could it possibly happen if it were to happen?

Yeah, that's a big question. And as someone, as I said, for me, I've been looking at gut microbiomes for. For 20, 20 some years, so it's been. And, and I would say that I saw the odd autistic patient up until probably three or four years ago. When and I started seeing a, a large number in clinic. And what, what was really good about that is that it allowed me to see quite some of the different patterns that you see in ASD community patients that you don't see outside this, this population. And I found that really fascinating because I've seen some patterns that have like 18 years of looking at microbiomes, never seen anything that's similar in other populations, that neurotypical populations compared to some of these kids on the spectrum. So I think there are some unique types of dyspotic ecosystems that I've seen in this population, as well as sorts that are similar to what you see in a more general population. I found this interesting too, looking at the research studies around this, trying to define what an autistic despotics ecosystem is. And I think maybe we'll start off talking about the research, because the challenge with the research is that there's little funding for it, which means they're using small study populations of like 20 people or 50 people or maybe 100 people, most in your study. And the differences between each individual's ecosystem is quite huge. And when you try to combine 20 people together and go, can we see a pattern that we see in us as kids and not outside that? No, the research has been very inconsistent in that regard. Although there's a few patterns that have shown up in different studies. And I found that fascinating because I've seen a few different patterns show up in my patients. It's not like all kids on the spectrum have got the same dysphotic picture. It's totally not that way. And I've broken this down to kind of probably six patterns that I see more commonly. So one would be what I'd call the excess propionate pattern. And that could be due to one of two different overgrowths. Actually, it could be due to Bacteroides overgrowth or Prevotilla overgrowth, and that both of those genera are avid propionate producers. And this is one of the unique ecosystem sorts that I've seen in ASD kids that I hadn't seen in any other populations was the Prevotella dominant ecosystem, where I've had kids whose ecosystems were dominated, like 80% Prevotella. And to put in perspective, the typical amount you'd see in a neurotypical population would be like a 1% or 2% or 0.5%. It's like, really, it was almost like a tiny player until you're working with ASD kids and going, my gosh, this is just crazy. Dominant in this ecosystem. And we know it's an avid propionate producer, but then so is Bacteroides. And people are generally, they either have one or the other. You can have other species dominate too, but you don't have Prel. And Bacteroides is usually one or the other. And Bacteroides dominant ecosystems are quite common, more widely speaking, in western populations, because Bacteroides is the omnivorous pig of the gut ecosystem that eats protein, eats bile, also eats a bit of fiber, also eats a bit of sugar, eats a bit of starches. It eats almost anything, but it doesn't have much competition when it comes to protein or bile. So people on a typical western diet, like the American diet or the Australian diet, we both call SAD diet, standard Australian or American diets tend to be low in fiber, higher in meat and fat, and those tended to result in bacterioidy's overgrowth. So that type of dysbiotic pattern I have seen much more commonly. Yes. So exopropionate. The other one would be just high levels of lipopolysaccharide or endotoxin load. And this could be due to overgrowth of Proteobacteria, which is a grouping of bacteria, a phylum and or also we include things like Prevotella, like Bacteroides, like Allostypes are three common genera that also contain endotoxin as well, or lipopolysaccharide. And essentially in that case, the word endotoxin kind of makes people think that these bacteria are like secreting toxins into your gut and it's like to attempt to make you ill or something. That's not what endotoxins really are, is that just like we grow hair, we grow nails. They grow this stuff called lipopolysaccharide on their cell membrane. So just fingers that kind of stick out of the cell wall. It just happens that this lipopolysaccharide is immensely pro inflammatory and can cause gut damage when absorbed. It can damage the blood brain barrier. It can actually change how our neurotransmitters are produced. It can change our blood sugar regulation, it can cause damage to our arteries as well. So that there's a lot of research looking at lipopolysaccharide, excess amounts produced in the gut and then absorbed as being key factors for Alzheimer's and stuff. I see on Parkinson's and cardiovascular disease more broadly speaking, as well as diabetes and obesity too, and autism and depression and anxiety. There's a lot of research looking at this pattern. So again this isn't one that's unique to the autistic community, but it is one that's relatively common, is having essentially an over growth of species. Gram negative bacteria in the gut, Gram negative bacteria essentially are all produce endotoxin. They're, they're, they differ in their capacity to induce inflammation. And that lipopolysaccharide from Proteobacteria is far more inflammatory than it is from Prevotella or Bacteroides or Allostipes. But if Prevotella makes an 80% ecosystem or Bacteroides makes up 70% of your ecosystem, you are shedding a tremendous amount of endotoxin into your gut on a daily basis, which then gets absorbed and causes inflammation everywhere. And it can even cos mitochondrial dysfunction as well. But that in itself can explain a lot of the issues that, that we tend to see in autistic communities in terms of behaviors etc, due to, you know, changes, damage the blood brain barrier, changes in neurotransmitter synthesis, changes in just that inflammatory tone as well. And mitochondrial dysfunction can all be linked to that as well as increased gut leakiness from that endotoxin load as well. Which then means you're absorbing more compounds from the diet or environmentally or more bacterial bits that you wouldn't otherwise be doing because the gut would be more intact. And I think that's another driver that comes from that too. Another pattern would be low butyrate production. And only certain, you know, some people out there, probably quite a few of them would know at least somewhat about the wonders of butyrate. And butyrate is a metabolic byproduct of at least some bacteria in the gut. Only some have got the capacity to make butyrate. And butyrate is a fantastic thing. It decreases gut inflammation, promotes healing it's main food source for your colon cells and help them to function properly. It's important for motility, normal motility, to keep your bowels moving the way that they should. But we also know that butyrate when produced in sufficient quantities, so more than your gut cells use as a food source, so that reaches the circulation and then can float around your body and have other beneficial effects like healing a damaged blood brain barrier, decreasing inflammation body wide, improving mitochondrial function. It's a pretty amazing substance, healing substance butyrate. And what a common pattern in the ASD community is having low levels of species that produce butyrate in the gut, which means low butyrate production as well, which means you don't get those benefits from, from butyrate that I Just laid out. And probably there's a couple more too. Like I think hydrogen sulfide gas, excess production too I think the research talks about and I've seen too in some of these patients high levels of the sulfavibrio, which is a hydrogen sulfide gas producer. And hydro sulfide gas also is capable of causing gut inflammation, improving gut, enhancing gut leakiness. So in a bad way damaging the nerves in the gut to make them more hypersensitive in something we as the medical community called visceral hypersensitivity, where the nerves become hyper responsive to even little stimuli can cause severe pain and discomfort. Even when it's a little bit of gas produced or a little bit of fiber rubbing against it, or some poo just sitting in that last bit of the colon. Even if there's normal amount of poo, it can feel tremendously painful when the nerves are really inflamed. And hardly sulfide gas can be contributor to that. And the last one I'll probably want to highlight is just is methane overproduction. And I think this fits in very much so with the constipation type pattern. Now there's one bacteria in the gut that is the main methane producer called Methanobrivibacter smithii. And occasionally people have got another methane producer, but it's usually Methanobiferbacter. And having some methane is a good thing. And I would want to flag this too, that having some Prevotella, having some Bacteroides are good things too. It's just when there's an overgrowth that's problematic. And it's the same with methane Bacter that when it's overgrown it's an issue because what Methenobibacter eats is hydrogen gas. And it eats four big bulky hydrogen gases and shrinks it down to one little dense methane. So having some present actually can help prevent bloating and distension type symptoms from gas because that big bulky hydrogen is shrunk to something else. However, when you've got lots of methane being produced, it slows down the gut. And this is what another pattern that I've seen. But an ASD community as well as outside the ASD community, but high methane and that can result in essentially slow transit time and constipation. And I do want to separate those out too because you can have people that do a poo every single day or even which, which wouldn't meet the definition of constipation, but the transit time can be very slow. So transit time is sort of like mouth to Toilet bowl. How long does it take for food to go from one end to the other? And I've had some patients and I remember having one patient that was doing every single day, never constipated her entire life. And if you there will be out there who are familiar with the Bristol stool scale, which is like a, comes from the, from the United Kingdom, but it's got like seven different types of poo and people generally be able to fit in and categorize themselves as, as one or two or three of those different types of poo. But anyway, she was type 4, which is like the perfect, you know, firm log, easy to pass, etc. That people, some people dream about. And her Transit time was 10 days. It took 10 days for food sheet to come out the other end. And you wouldn't get that by. Because she's not constipated. Yeah. But in that 10 days there's a lot of absorption of stuff from her poo that was giving her headaches and fatigue and brain fog and just general gut discomfort as well because the fecal matter is all built up around that. So I think. And methane was, is a common driver of that. Yeah. So I think when people have that slow transit time, which can manifest as constipation, but not always, they can get one more gut discomfort and pain and bloating and distension. And it can also manifest as reflux because of the lack of movement due to that, that methane production. But you can get body wide effects too because it kind of will essentially enhance the absorption of these, you know, compounds your body's trying to get rid of via the poo as well as more bacterial metabolites as well. Because when it sits there for 16 hours, things move through pretty quick. But if something's there for five days or six days or 10 days or. Gosh, the worst I've had was 25 days for that transit time test there. So we're being a lot of crap from their crap to put it. Yeah.

Oh. So yeah, that's really great explanation. Thank you for that. So I wanted to touch on, I wanted to get to the point of kind of going over different modes of treatment. But before that I wanted to touch on what your view is for cesarean section and how does the ASD biome that you see, how do you think that it gets to that state, do you mean? So there's, there's definitely a correlation that we've seen with C section and asd. And just because you have a C section doesn't mean you're gonna have asd. But there seems to be some correlative link there with the biome antibiotics. I mean, is there a prescription that you can think knocks things in the wrong direction?

Definitely I would. I mean, there are differences in different antibiotics, I obviously, but as a, as a whole broad category, yes. And I've had a lot of kids that I've been working with where the turning point was antibiotic course or courses for ear infection or for throat infections. You know, development is going along fine, started getting sick and then gave one of course antibiotics, another, another and then boom, after the third course or even the second course, sometimes behavior changes and they start regressing and all of a sudden they've got a child on the spectrum who wasn't before. So. And I've seen that as a pretty common pattern amongst my population. So antibiotics are certainly problematic in that regard. And proton pump inhibitors. So the class medications used to treat reflux also, we know cause massive alterations to both the small bowel ecosystem, but the colonic ecosystem too, which are not widely promoted yet. This is commonly given to kids with reflux. Infants with reflux are given this medication even though one clinical trial show it's of limited efficacy and doesn't work any better than placebo, but still commonly done. And it causes increase of food allergies as well. Well, but then you're also getting this disparate state with it too. And you're right about the C sections, and I think formula feeding would probably fit in that category too, is that we're severely changing that initial, initial seating event, you know, and that has consequences. And there's tons of studies showing there's a range of negative health outcomes associated with C section birth or formula feeding versus, you know, the optimal vaginal birth and breastfeeding. And a lot of that's got to do with changes in the growth pattern of micro, of the microbiota where the bacteria come from. You know, C section born kids tend to, I mean, their skin bacteria actually doesn't belong, it doesn't come from their parents, it comes from hospital staff that they're working with, you know, which I think is just mind blowing and scary, to be honest. Whereas normally we would pass on our skin floor from generation, generation through the birth process, but not IC section. You've picked up the nurse, that nurse was their, their skin floor is now on your family line and will be passed down from generation to generation potentially from that point. And obviously gut floor changes from that, that point too. That, that there seems to be something pivotally Pivotal about passing through the birth canal. And even though the vaginal ecosystem that they're getting exposed to, those species aren't dominant in a colonic ecosystem. They sense that they're always seen as trailblazers and they, they cut a certain path in a certain direction. And if we take that away, you have a different path going a different direction. And it's. This develops differently that ecosystem. And I do think you can, you know, things like breastfeeding right away and exclusive breastfeeding will offset at least a portion, if not a lot of that. But you get these situations where obviously there's C sections and then at post C section, the capacity to breastfeed dips because they're often, they're given medications and the Bob's given, you know, the mom's given a dose of antibiotics at that time. And if they do breastfed, the antibiotics are coming through the breast milk at that time. So there's a few, few aspects that I think further complicate things when it comes to, to C section birth. But we know that the breastfeeding rate is far less post C section. It is compared to natural birth because of the medications and other things impact milk flow and then that can lead to sore nipples and feeding difficulties and then the whole pattern can run right on and on.

Awesome. So in terms of, you know, treatment, if I have a dysbiotic biome, what things, you know, would be appropriate? Would antibiotics ever be appropriate? Would they ever be part of the overall plan? Can you do it solely with probiotics, prebiotics, diet, you, you know, things like that. We had a question come across about helminth therapy, you know, kind of parasitic worms that do positive, you know, reinforcement on the gut. Is there any, are any of these things kind of a.

No, No.

I mean, do you, do you like any of these things? How would you go about doing it? Generally?

Yeah. Okay. I mean, I'm immensely cautious around antibiotics and maybe that comes from, you know, I did a systematic review where I grabbed every study that looked at antibiotics and their impact on the gut microbiota back in the early 2000s. And I've been avidly keeping up in that area since then. And the impact of antibiotics on the gut ecosystem is, is when you look at it in detail is to me quite scary. And does that mean that I, I won't use antibiotics for life, life or limb threatening infection? No, I will. But I do think that we have to be cautious around the use and be prudent around the use and save them for when they're saving lives limb and using them less for experimental well, let's just try out and see the impact because they can cause irreparable damage. There was one study published in Gut 2019 I think it was but us one single course of an IV antibiotic caused the extinction of nine species from that person's gut ecosystem. Nine wiped out forever from a single course. You know, so I think we have to keep this in mind that it's not an intervention that you can come back from in that once it's done, it's done and the ecosystem is going to be permanently changed potentially in a big way. And maybe there could be some beneficial aspects of that in certain people in certain situations. But I worry very much about the collateral damage that occurs with that process. And I suppose on the counterpoint of that, as a clinician who's been using and looking at them, at the research around changing the ecosystem with food, with making dietary changes, with prebiotics, with probiotics, with herbs. I mean this is what I've been researching and looking at and working with patients with, with 20, 20 years is you can make dramatic, absolutely huge shifts in ecosystem composition using those tools, you know, so I think that personally I would put antibiotics as like there's a, as a big gun that maybe, maybe if you try prebiotics, probiotics, dietary change, herbal medicines, all these things and then in the ecosystem doesn't shift, then okay, then maybe you pull out a bigger gun knowing that it may cause irreparable damage as well as some benefit that comes with it too. But I just think there's such a great capacity to shift the ecosystem. And I've been working with as a core part of working with patients has been for me for 15 years of changing ecosystems, as you can see, dramatic shifts using those tools that I seldom see the need for having to use an antibiotic to do so. And really the only way of potentially repairing that damage post antibiotics is doing fmt, you know, and yeah, which I'm sure there'll be capacity chat more more but later on. But I think people have to realize that you can't just pop a probiotic pill if you've lost nine species, you've lost your subdigranulum and your aneroid stipes and your rheumococcus. Let's say taking a bifidobacteria supplement is not going to fix that. It's not going to replace that. It's not going to permanently recolonize with the species that are lost. They're lost. So I think we have to keep that in mind when considering interventions.

Just jumping off of that. Do you think that for. I mean, obviously there's. There's people that have autism that are not C section.

Yeah.

You think that those that you know are C section and have autism, that they are the ones that might benefit more from an FMT or might need it just because there might be missing species in. Or there's more likely that there'll be missing species in there.

It's a great question, Alex. And I think there's lots of unknowns in the cat in the realm of fmt and who will get the most benefit from it. I can say from analyzing the microbiota of a lot of ASD kids now is that there are a few that look really lovely, but most don't. And the ones that don't, I think there's a lot of work you can do by changing that. And then that seems to result in changes in behavior and cognition and physical traits, et cetera. So I've been heartened by seeing how much change you can make without doing something. Probably I'd see more drastic like an fmt and it's. But trying to optimize that person's ecosystem when we can, using prebiotics, diet and herbs as the main ways of doing that, and probiotics as well now. But I mean, you make a good point because I have had some people that were like vaginal birth, breastfed, never, of course, in antibiotics in some kids, no medications ever. And still on the spectrum. So these things increase risk. We know from a research perspective and we can understand the rationale or the physiology behind how they might increase risk. But there's certain people who. Who have developed ASD despite doing all the right things from that earlier. Well, having none of those interventions happen, I suppose I don't want to use the word right because people are doing the best they can for their kids and they're following health advice, etc. And births just don't always go according to plan and breastfeed doesn't always go according to plan. So I just want to make sure I'm using the right words. They're not, because I fully understand that people are always doing the best they can to help their child on the best advice they have at that time point, you know, and we all learn, you know, we all do things differently with our older kids. We do our younger kids because we have learned along the way. Yeah, but I do think there's. There are people, as I said, that that in that case and in that person maybe ecosystem isn't the biggest driver. You know, I don't, I think that the egosism is a big driver for a lot of kids on the spectrum. But I wouldn't even put it as 100 of every child on the spectrum has got dysbiosis and needs microbiota alteration because I have seen some ecosystems that were, were quite lovely and the child was still on the spectrum. But so I mean I think that's what I'd look at in terms of whether an FMT or not. You might go, okay, let's look at what you've got, let's look at your history, let's try to optimize the ecosystem and let's see the results. And for me I would put an FMT on the end of that if we one the ecosystem was not so responsive, you know, we weren't able to increase the diversity, the richness didn't improve, the levels of beneficial bacteria didn't go up and the path of bonds didn't go down and, or there were certain species that were still were lacking like Bifidobacteria or Akkermansia then. Okay, yeah, I think FMT definitely would have a role to play. But I do have a degree of caution that I prefer to do the other interventions first and see what impact we have for most populations before jumping in with an fmt. And I think that's partly to do with cost because FMTs in general are more expensive, more labor intensive intervention. But I still think there's a small risk with FMT of taking a step backwards because you're introducing a new ecosystem to a new person and there's still unknowns there, but the best way of matching and maybe 20 years from now we'll do this far better than we do now. You know, and I've seen worked with kids who've had FMTs on the spectrum and they jumped gigantically ahead in so many different ways. So I've personally seen that benefit too. But you do see the occasional patient and these ones stick in your brain too because they think of one who deteriorated post FMT or post it was the second donor, the first donor, the kid, the child took giant leaps and forwards going great gangbusters, so much improvement and they changed to another donor. And then 25 hours after the SEC, first person's or the second person's FMT, the first dose, there was a dramatic regression and they were back to sort of square one or I think about moms to death even below Square one where they started with before, you know, so I've, and I think this is rare and I certainly don't want to freak people out because I don't think it's common, but it's just a possibility and I prefer to work with what we can do to optimize the ecosystem first. Um, and then if that isn't successful, then have a fallback option of fmt. And I think we're, we are learning more about trying to match, match donors too. And I remember I working with one patient who had brought me three different donor stools to look at and go, which is the best donor for my child? And I could look at the child's ecosystem, I could look at the three donors and go, okay, well donor two is going to be the best one, best fit for, for them. Based on our current knowledge. We don't know everything what we know now. As someone who's been in this field for 20 years, geez, I know a hell lot more now than I did 10 years ago and 15 years ago and I'll know more another 10 years. What I do now because the science is evolving, the techniques and tools that we're using to see the ecosystem and the connections are evolving. We're learning more about species that were not named bugs like Phecalobacterium prosnitzii was not even known 15 years ago. Yet we now know it's a key player that's one of the dominant butyrate producing species that we generally want more of in people's guts. And we now know some of the tools we can use to improve populations of that, like prebiotics for example, that do so. But there are other species that you get that readout from thrive or from Cosmos ID or microbar or something and you've got maybe 150 species present and there's a lot there. We have no idea what they do. No one does, you know. And this is where we're going to be constantly learning because we're going to be looking at what that species is, what it does, what role it might play, how might interact with others. That, that kind of research is evolving and moving forward at quite a good pace, thankfully.

Awesome. So we have so many questions coming across the bottom. I'm hoping that you'd be able to answer them offline in the future at some point because there's some great questions on there. I'm not sure I'll be able to get to all of them. What I did want to ask though is in terms of those positive Things that you think of people can introduce, maybe like Saccharomyces boulardi or green tea extract. Can you comment on some of those things that people might be able to with the addition of a stool test, add in that will generally normalize, make things more diverse, but balance the diversity.

Yeah, I think there's certain strategies we can do or implant that we know in general, enhanced growth of beneficial species, decrease growth of pathobion and improve diversity of an ecosystem. And I think ideally, particularly in this community, it makes sense. I would recommend actually doing a test first and then trying to implement things that are a bit more individualized for that, for that, for that child or that, that patient. Because I, I think one thing I have noted with, with ecosystems and ASD communities, that they tend to be more dynamic and pliable and that they're more changeable and interventions can make really big shifts to it. And that can be a plus and a negative plus in that, okay, if they're immensely, we can change things, but it's also like we have to be aware of what we're using, the tools we're using for this person to best individualize it. We get the best outcome. I think that that makes it more clear, which is I'm probably more cautious around ASD microbiome modification than I am. And definitely the neurotypical population where I'm like, okay, how do we general health, general population, how do you make a healthy ecosystem? Eat more fiber, eat more plants, eat more. Avoid all processed food, avoid artificial sweeteners and emulsifying agents that strip away your protective gut layer. Eat a rainbow food so you'll have lots of purples and reds and blacks in your diet because those polyphenols nurture good bacteria. And I think those same strategies we can certainly use in ASD populations. But I think it's just being aware of that sometimes, particularly a Prevotella dominant ecosystem might respond in a different way than a Bacteroides. Don't one and that's very much the case that that approach works well for Bacteroides type populations. And even things like I'd say Inulin, for example, can, can work to decrease Bacteroides, which is great, but it can also increase Protella. So it's this thing of going if you don't know, then. And I think this could explain at least it's my personal hypothesis of why some people on Nemcheck protocol get amazingly good results and others can get actually get flares. And personally I think it's got a lot to do with that Bacteroides prevotella issue in that if you're Bacteroides dominated, inulin will be fantastic. And you know, I've been using inulin and other probiotics to prebiotics, sorry to decrease bacteroides for 20 years in my practice. They're very effective tools to do so. But if you're Prevotella dominated then you may actually end up encouraging Prevotella even more so with that inulin and that could increase propionate production even more so and hence cause cause of flare. So I do have more caution around certain tools without looking at the ecosystem system first in the ASD community. But other things like Saccharomyces cerviaceae, Varadi boulardii, which is it's long but correct name I think is generally quite a safe tool to work with. And I think even green tea extract too, that I love, epigallocation Gallate, which is the main polyphenol founded green tea that we know has got selective antibacterial activities. So it targets pathogens and pathobionts that we don't want and actually encourages levels of beneficial bacteria. Plus it breaks down fungal biofilm from things like Candida. So it's. And you're getting the antioxidant effects from the, from the green tea extract too. So I'm a big fan of that and I think it's perhaps can be used more, more widely in the community than some interventions that I have perhaps more caution around. But I do think that this population is also more susceptible to die off reactions too, generally speaking compared to neurotypical populations as a whole. So I think there can be some caution around how quickly one changes the diet, how quickly one introduces prebiotics, the dose they start with. And even things like green tea or Saccharomyces too is like okay, well maybe it's starting off very slow, lower dose or whether it's giving some other things alongside to help protect the nervous system from potential inflammatory reactions or giving some sort of binding agent alongside those antimicrobial approaches. And you know, prebiotics are kind of anti antimicrobial, they're just very targeted. You know, they're, they're not directly targeting pathogens or pathobions, but they are feeding beneficial bacteria who change the environment. So when that's, it's not conducive to the growth of things like Bacteroides or Proteobacteria and their populations go down, but when they go down, they're dying and they're leaving their endocene out there. So I think sometimes there has to be to be a caution within with, with how quickly some of those things are introduced to not everybody. But I do think that a higher proportion of kids in this area have got susceptibility to die off type reactions than other populations.

Jumping off of the Candida fungal overgrowth seems to be a significant problem in some of the kids with asd. Not necessarily always Candida. But you know, if you could just talk about the importance of the microbiome because typically what happens is that, you know, kids or people with autism, they might take a strong antifungal and they might see positive effects to that. But what comes in after that the same kind of, you know, thinking of an antibiotic with the microbiome. Are there positive yeasts that do good in the body and is there ever a dynamic of where the microbes live in the gut? Like could you have a misplacement of yeast before bacteria, vice versa that you're not able to really see on a stool test? And that is also causing issues spatially.

I think you can certainly have overgrowth in different parts and small intestinal bacterial overgrowth or SIBO or you could or sifo, small intestinal fungal growth would be probably accord examples of that. Where you've got, you're supposed to have low levels of bacteria or fungi probably growing in those in that area of the small intestine. But you have these overgrowths within cause problems by either causing intestinal damage, which occurs in some cases, but certainly competing for food and producing, you know, gas and metabolic byproducts and also producing releasing things like endotoxin depending on what's present in the gut. I mean you bring up some interesting points around the microbiome because I think really we're in early stages of really discerning what it is, what's, what's healthy, what's normal. And you know, some of us looking at the gut bacterial ecosystem for 21 years, I mean really the data on the microbiome using modern techniques, so again using molecular DNA or RNA based approaches, is it probably only goes back to like 2015 or so that they really researchers gone oh well let's look at this now. And there's still a lot of discussion about what's normal, how many species of fungi are present, what important roles that they're playing. And it certainly is clear on our current data is that fungal species do play important roles in human health, just like the bacterial components do, just like protozoa in the gut, often playing an Important key roles and we're still defining what, what they, what they are in all those three areas. But, but certainly in the area of fungal microbiome we are. So I do have some cautions around using, using powerful anti antifungals. Unless you know, again, there'll be time and place for such things, but I can't help but just have some cautions around it because we're interfering with the ecosystem. We don't know that much about now and we don't even know what the impact of that intervention is.

Now.

There was one very interesting study. It was a, it was a mouse study, a rat study, I can't remember which one, but it was definitely an animal study where they gave systemic like a antifungal or as an oral pill. But one of those ones that acted body wide and I can't remember the name top of my head, it's just totally slipped out, it'll probably come to me later. But they, they were curious, they're like, okay, what impact does it have on the fungal microbiome and what impact does it have on the microbiota, the gut bacteria populations as well? Because we tend to think of, okay, if it's killing fungi, the bacteria will be left intact. But that's not what they found. They found that there was a initial massive decrease in fungi growth, but essentially the speed the species of fungi that were resistant to that antifungal bloomed after pretty soon afterwards and they dominated the same level that to the actual amount of fungi didn't change, but the species dominated, did that the ones that were susceptible were dropped down or died. And the ones that weren't just took over the space and the ecosystem because the ecological niche was still present. That in itself was an interesting finding. But the other interesting finding was that the bacterial ecosystem shifted considerably too. And this was less expected. And it was essentially because of the cross, the reactions between the lovely, the healthful interactions, the beneficial interactions between the different fungi and bacteria. And we essentially knocked out a bunch of species of fungi. The bacteria that were reliant on that interaction to thrive dropped out too. So there was actually massive shifts from a bacterial perspective too. And it's just that we're at such early days of looking at, okay, what happens when we get this antifungal? What happens to the bacterial ecosystem? What happens to the fungal ecosystem? Is it targeting and maybe we're targeting fungi that's living in the sinus cavity or back of the throat or in the lungs or something even maybe not in the gut, but the medications coming into the gut and changing things there. So it's just, I think when we're working in areas that we don't necessarily understand the repercussions of our interventions. Well, I have a degree of caution around it because I just, I suppose I've got some fear having seen the role of antibiotics and causing species extinctions. I would hate to see us go down the. Let's give every ASD child antifungal to see if it helps. Yeah. End up causing, you know, extinction level events that are virtually very challenging to come back from. Once a species is extensive, it's extinct unless they can pick it up from another fecal exposure, essentially.

Very interesting. I think we have time for one last question. I was going to try to pick two of them and put them together that came across there. So someone had asked a question about probiotics. You know, what role do they have in shaping the biome? And you know, from what I understand is I think that they might have a role, but more prebiotics and diet probably can go a longer way. Not to say that probiotics can help, but then jumping off of that and then the kind of antifungals there. Are there some herbals that, you know, you might recommend or you might use, you know, something like a pomegranate husk or, you know.

Yeah.

That have an antifungal property that, you know, don't nuke the whole gut, so to speak.

Yeah, good, good, good. Both of those are good questions. And given that we ended with the fungal. And I'll start there, I think things like garlic. Garlic. I mean, I looked at some of the collateral damaging impact of whole medicines of the microbiota as part of my PhD. Garlic was, was, was very benign and so is green tea and so is pomegranate has, which is the skin of the pomegranate fruit. So here are three things that are actually quite potent antifungals and selective antibacterials that tend to target our pathogens and even pathobionts well, but leave the good guys intact. And I've seen that in my stool testing with patients over the last decade as well from using these tools as we don't cause a worsening disbiotic ecosystem. So I think there are certain tools we can use to shift that, both bacteria and certainly from a fungal perspective too, that are going to be more selective. Now those things are going to work in the gut, but they're not necessarily going to work. They're not going to work for Aspergillus growing in the sinus cavity or in the lungs or something. Garlic will have probably some usefulness there, but green tea and pomegranate, essentially none. Now the first part of that question was around probiotics. And yet their capacity to shift ecosystem is far, far less than changing one's diet dramatically. You're taking prebiotics. Those things change an ecosystem in much greater degrees of, in much broader areas than you'll get with, with probiotics. It's not to say I don't use probiotics. I do, but often for very specific things like I might use a probiotic strain that speeds up transit time in someone who's got constipation and slow transit time. I'll use saccharomyces to speed up gut healing and to help regenerate, you know, damaged small int bio enterocytes and people who've got like a enhanced leaky gutter, enhanced per, enhanced permeability. So there I do use probiotics lots as tools, but they are more limited in their capacity to shift the ecosystem compared to dietary changes and prebiotics, particularly from a bacterial perspective, you know, and I do use, you know, saccharomyces supplements for fungal things too, for that matter. And in which case it does actually target, you know, the specific potential overgrowth of a fungal organisms as well. And the lactopathy reuteride DSM17938, which is sold as Biogaia, does target methane quite effectively too. So, you know, yes, there are selective probiotic tools which are definitely useful adjuncts. But I think if you're looking at making big shifts to the ecosystem, their impact is far less than what you get with prebiotics or diet.

One quickie, someone had asked about MCT oil and using that in terms of an antifungal. Do you think that that has any negative consequences?

I think as far as I'm aware, things like caprylic acid or undecylenic acid, caprylic acid is, I think the compound in MCT oil that people would be wanting to use are more selective and what they're doing and I haven't read or seen in patients that I've might have used those tools any evidence of causing a dysphotic shift in the bacterial components of that ecosystem.

Awesome. This has been great. I really, I really appreciate it. I learned a lot here. And you know, any of the questions that we didn't get to, we're going to pass on to Dr. Horlick and in his free time he'll be able to, you know, send some responses, but I really appreciate your time and your willingness and your expertise, you know. Found this very interesting.

Oh, good. I'm glad, Alex. It was nice. Nice chatting. Actually, I enjoyed it, too.

Awesome. All right, well, good morning there and good night here on the East Coast.

Yes. Take care.

Take care. Bye. Bye.